This invention relates to both a catheter device and a method of using the catheter for inserting living cells into the body for the treatment of neurological disease.
Deficits in neurotransmitters and other active biologic factors have been implicated in the etiology of various neurologic diseases. Parkinson""s disease, for example, is characterized by a deficiency of the neurotransmitter dopamine within the striatum of the brain, secondary to damage or destruction of the dopamine secreting cells of the substantial nigra in the mesencephalon. To date, however, direct intraparenchymal delivery of purified or synthetic dopamine, or its precursors, analogs or inhibitors has not demonstrated clear therapeutic benefit. However these efforts have revealed various problems associated with drug delivery, stability, dosage and cytotoxicity of these agents.
In other disease states, biologically active macromolecules are believed to provide benefits by ameliorating the disease process or stimulating responses that result in therapeutic improvement. For example, models of Alzheimer""s disease have been shown to benefit from the introduction of protein growth factors in vivo. Models of primary brain tumors have demonstrated therapeutic responses in response to the introduction of cytokines designed to stimulate the immune response against the tumor cells. However, it is difficult to provide reliable continuous delivery of these agents in actual clinical settings.
Implantable miniature osmotic pumps, such as disclosed, for example, by U.S. Pat. No. 4,475,916 to Himmelstein, et al. have been used to provide a continuous supply of drugs or other active biologic factors to the brain and other tissues at a controlled rate. Reservoir limitations as well as drug solubility and stability have, however, restricted the usefulness of this technology. Controlled sustained release of dopamine has been attempted from within bioabsorbable microcapsules, such as disclosed by U.S. Pat. No. 4,391,909 to Lim, U.S. Pat. Nos. 4,673,566, 4,689,293 and 4,806,355 to Goosen, et al., U.S. Pat. No. 4,803,168 to Jarvis and U.S. Pat. No. 4,883,666 to Sabel, et al. However, this method, appears to rely on surface erosion of the bioabsorbable polymer, which is in turn influenced by various hydrolytic events, thereby increasing the likelihood of drug degradation, and rendering predictable release rates difficult. A further problem appears to be attributable to limited diffusional surface area per unit volume of larger size microspheres, such that only a limited volume of cells can be loaded into a single microcapsule.
Exemplary of an implantable microporous devices for drug delivery are also known from U.S. Pat. No. No. 3,993,072 to Zaffaroni, U.S. Pat. No. 4,298,002 to Ronel, et al., and U.S. Pat. No. 4,309,996 to Theeuwes. U.S. Pat. No. 5,104,403 to Brotsu, et al., discloses a vascular prosthesis with a low porosity outer material and a inner synthetic tubular mesh. The semi-permeable microcapsules contain hormone producing cells that are placed between the outer material and the inner mesh. Blood flows through the vascular prosthesis allows for metabolism of the cells and circulation of the hormones. U.S. Pat. No. 5,171,217 to March, et al discloses a method for delivering drugs to smooth muscle cells lining blood vessels utilizing balloon catheter procedures and direct pressure delivery. However, the Brotsu et al. device does not involve the MRI-guided intraparenchymal delivery and monitoring of cell therapy.
Macroencapsulation, which generally involves loading cells into hollow fibers and then sealing the ends of the fibers, has also been used to deliver therapeutic drugs into the central nervous system. Exemplary of the macroencapsulation approach to drug delivery is U.S. Pat. No. 4,892,538 to Aebischer, et al., which discloses methods for delivery of a neurotransmitter to a target tissue from an implanted, neurotransmitter-secreting cell culture within a semi-permeable membrane, wherein the surgically implanted cell culture device may be retrieved from the brain, replaced or recharged with new cell cultures, and re-implanted. U.S. Pat. No. 5,106,627 to Aebischer et al. additionally discloses a method for the combined delivery of neurotransmitters and growth factors from implanted cells encapsulated within a semi-permeable membrane. However, while these methods may offer the advantage of easy retrievability, the encapsulation of cells within macrocapsules implanted in the brain is often complicated by unreliable closure of the reservoir resulting in inconsistent tresults.
Studies utilizing implantation of cells capable of producing and secreting neuroactive factors directly into brain tissue have demonstrated that Parkinson""s disease symptoms can be improved by transplanting fetal dopamine cells into the putamen of the brain of patients with Parkinson""s disease. U.S. Pat. No. 5,487,739 to Aebischer, et al. discloses a cell therapy delivery method utilizing a cannula, obdurator, and implantable cells, wherein the biologically active factors diffuse into brain tissue through an implanted semi-permeable membrane. U.S. Pat. No. 5,006,122 to Wyatt, et al. discloses an apparatus for transplanting tissue into a brain, comprising a stereotactic device for inserting a guide cannula to a target location within the brain into which a second cannula containing the tissue transplant is inserted and the tissue is deposited.
However, a major problem for this emerging therapy is the limited and variable supply of human fetal tissue and the societal issues associated with its use. Fetal pig neural cells have also been shown to survive in an immuno-suppressed parkinsonian patient. Improvements in the quality of transplantation also appear to be emerging. Recent studies have demonstrated that somatic cell cloning can efficiently produce transgenic animal tissue for treating parkinsonism. It is also possible to surgically remove neural progenitor cells from a patient, grow the cells in culture, insert therapeutic genes, and then replace the transfected cells back into the patient""s brain.
Thus, there exists a need for an improved method to deliver cells that can produce biologically active factors to a target region of the brain. In addition, there is a need for a method to monitor non-invasively the ongoing viability of the cell implant, in particular to determine whether the cells are adequately perfused by the local microvasculature and continue to provide sustained and controlled delivery of the deficient biologically active factor.
The catheter of the present invention delivers cells, cell suspensions, or solid tissue grafts into the Central Nervous System (CNS) and in particular into a targeted region of the brain. Although the invention is disclosed in the context of the treatment of the brain it should be understood that spinal cord, and other target regions of a patient suffering from a debilitating neurologic condition or syndrome are amenable to the devices and techniques described herein.
The catheter device facilitates the use of imaging methods for the local and controlled delivery of a biologically active factor, which can augment or replace the function of dysfunctional constituents of the brain, spinal cord or other tissue without causing trauma.
The device and method of this invention facilitate and permit an imaging method for monitoring non-invasively whether the cell implant provides sustained and controlled delivery of the deficient biologically active factor.
Catheters according to the invention provide structures that shade or shutter certain apertures at the distal end of the catheter, thus allowing the clinician to more precisely regulate the delivery of diagnostic and/or therapeutic agents into the target tissues. The catheter architecture may also be used for controlling the amount of illumination that is delivered into the CNS through an optical fiber inserted through one of the catheter lumens. In this instance the light energy is used for assaying cells tagged with the green fluorescent protein or related materials.
In the method of the invention, conventional MRI navigation procedures are used to guide an MR-compatible access device and a catheter containing the cell implant to a target location in the brain or other tissue. Following the positioning of the catheter tip at the target location, delivery of the cell implant is monitored using high-resolution MR imaging in combination with optical or other imaging methods. Further in the method of the invention, high-resolution MRI methods may be used to non-invasively evaluate the viability of implanted cells.